This invention relates to electrochemical oxidation of dihydrocarbyl disulfides in the presence of arenes, and to production of hydrocarbylthioarenes. This invention also relates to certain novel adducts and to the formation of these adducts.
Electrophilic thiation is typically accomplished by the use of a sulfenyl chloride, disulfide, or thiosulfonate, with a Lewis or Bronsted acid. Silica gel has been used to catalyze the reactions of sulfenyl chlorides with arenes, while zeolites have been used for catalysis of hydrocarbyl disulfide reactions with phenols.
A method has been reported for thiation using electrochemically generated sulfenium ion in dichloromethane, with low yields; see Do et al., Tetrahedron Lett., 1998, 4657. The sulfur electrophile produced could effect substitution with highly activated phenols in 26-77% yield, but with the less activated anisoles the yields were only 11-35%.
Glass and Jouikov, in commonly-owned, copending application Ser. No. 09/302,908, filed on Apr. 30, 1999, now U.S. Pat. No. 6,207,838, describe electrooxidation of organic disulfides where thiation of arenes is accomplished in liquid SO2. Although ahighly effective process, it does involve use of low temperatures and/or elevated pressures to keep the SO2 in the liquid state during the process.
In both of the foregoing electrochemical methods, an electrophilic thiating agent is prepared electrochemically and then, in a subsequent step, it is added to the arene substrate in order to produce an organothiated arene. Such procedure requires that the electrophilic sulfur species persist until added to the arene. Although the Glass and Jouikov method gives higher yields than the Do, et al. method, the need for using low temperatures or high pressures to keep SO2 in the liquid state is a shortcoming of that process.
It would be a considerable advantage if a way could be found for electrochemical organothiation to be achieved that avoids the need for low temperature and/or pressurized operation.
This invention provides efficacious technology enabling production of organothiated arenes in good yield without the need for low temperature or high pressure. This invention provides for electrolytic oxidation of an organic disulfide (R2S2) in the presence of an organothiatable arene substrate in a liquid phase mixture. Organic electrochemical solvents in combination with a supporting electrolyte are used as the medium for the electrolytic oxidation, and thus the low temperature and/or elevated pressure conditions required for liquid SO2 are avoided. By making the substrate one of the initial reactants during the electrolysis step, the problem of the instability of the electrophilic sulfur species formed by the anodic oxidation of the organic disulfide is averted.
Accordingly one of the embodiments of this invention is a process which comprises subjecting an organic disulfide in which the organic groups are primary or secondary organic groups to anodic oxidation in a solution formed from (i) an organothiatable arene containing only aromatic unsaturation, (ii) an organic electrochemical solvent, (iii) a dissolved supporting electrolyte, such that an organothiated arene is formed.
For some aromatic compounds, even controlled potential electrolysis results in overoxidation of the organothiated arene substrate and this can result in production of excessive amounts of unwanted by-products. Furthermore, the acid produced in the reaction can also result in production of excessive amounts of unwanted by-products. For example, when subjected to controlled anodic oxidation, arenes having a cycloolefinic moiety in the molecule such as acenaphthylene polymerize and form copious amounts of insoluble polymeric precipitates. However, pursuant to this invention, the problem of overoxidation and sensitivity to acid can be minimized, if not eliminated, by conducting the electrochemical reaction in the additional presence of an organic nucleophilic base, such as pyridine, with the resultant formation of novel adducts which are more resistant to oxidation, and which are highly useful as they can be subjected to eliminative aromatization in a subsequent reduction step, resulting in good yields of the desired thiated aromatic compounds. Thus, in the case of acenaphthylene, the inclusion of pyridine in the electrochemical reaction mixture overcame the polymer formation problem and resulted in the formation of an adduct which, upon electrochemical eliminative aromatization, gave 1-methylthioacenaphthylene in a yield of 76%.
Accordingly another of the embodiments of this invention is a process which comprises subjecting a dihydrocarbyl disulfide in which the organic groups are primary or secondary organic groups to anodic oxidation in a solution formed from (i) an organothiatable arene, (ii) an organic electrochemical solvent, (iii) a dissolved supporting electrolyte, and (iv) an organic nucleophilic base such that an adduct is formed in which the aromatic ring of a mononuclear arene or an aromatic ring of a polynuclear arene is dearomatized and is substituted on the dearomatized ring by an organothio group and a cationic organic base.
Such adducts are new compounds having good stability particularly towards oxidation. Thus a further embodiment of this invention is an adduct in which a cycloaliphatic ring is substituted by an organothio group, and by a cationic organic base, and wherein, optionally but preferably, the cycloaliphatic ring is attached, preferably fused, to at least one aromatic ring. The adducts of this invention can be recovered from the reaction mixture by conventional means for use, for example, as chemical intermediates. To illustrate, the adducts can be subjected to eliminative aromatization so as to form an organothiated arene.
Still another embodiment of this invention is a process which comprises:
A) subjecting an organic disulfide in which the organic groups are primary or secondary organic groups to anodic oxidation in a solution formed from (i) an organothiatable arene susceptible to overoxidation, (ii) an organic electrochemical solvent, (iii) a dissolved supporting electrolyte, and (iv) an organic nucleophilic base such that an adduct is formed in which the aromatic ring of a mononuclear arene or an aromatic ring of a polynuclear arene is dearomatized and is substituted on the dearomatized ring by an organothio group and a cationic organic base; and
B) subjecting said adduct to eliminative aromatization such that an organothiated arene is formed.
Yet another embodiment of this invention is a process which comprises subjecting an organic disulfide in which the organic groups are primary or secondary organic groups to anodic oxidation:
A) in a solution formed from (i) an organothiatable arene having an oxidation potential at least about 150 mV higher than that of the organo disulfide, and (ii) a liquid organic dipolar aprotic solvent, such that organothiation occurs and an organothiated arene is produced; or
B) in a solution formed from (i) an organothiatable arene having an oxidation potential that is lower, equal to, or less than 100 mV higher than that of the organo disulfide, (ii) a liquid organic dipolar aprotic solvent, and (iii) a nucleophilic organic base, such that an adduct is formed in which (a) an organothio group and (b) a molecule of the organic base are both bonded to a cycloaliphatic moiety derived from the arene; and
subjecting said adduct to eliminative aromatization such that the organic base is removed from the adduct and the cycloaliphatic ring is aromatized whereby an organothiated arene is formed.
For example, in acetonitrile, dimethyl disulfide shows an irreversible first oxidation peak at 1.05 V vs Ag/O.1M AgNO3 in acetonitrile reference electrode using the technique of cyclic voltimetry. The oxidation peak of anthracene is about 400 mV more positive than that for dimethyl disulfide. Consequently, pursuant to this invention, dimethyl disulfide can be selectively oxidized electrolytically in the presence of anthracene to produce the organothiated product, 9-methylthioanthracene, in very good yield.
These and other embodiments and features of this invention will be still further apparent from the ensuing description and appended claims.
As indicated above, in the practice of this invention some arenes can be electrochemically organothiated in one step to produce an organothiated arene, Ar(xe2x80x94SR), where n is typically 1 but can be 2. A good illustration of this is the controlled electrochemical oxidation of dimethyl disulfide in the presence of anthracene as described in Example 1 wherein without use of a nucleophilic organic base, 9-methylthioanthracene was produced in 74% yield, along with an 8% yield of 9,10-di(methylthio)anthracene. While some overoxidation occurred, the extent of overoxidation was not excessive. On the other hand, with other arenes it may be desirable, if not essential to perform the operation in two steps whereby in the first step the electrochemical organothiation is conducted in the presence of a nucleophilic base so that an adduct of this invention is formed. In the second step the adduct is subjected to eliminative aromatization such that the organic base is removed from the adduct and the cycloaliphatic ring is aromatized whereby an organothiated arene is formed. Thus in any case where it is desired to form an organothiated arene (instead of an adduct of this invention as the end product), and the behavior of the initial arene towards anodic oxidation under suitably controlled conditions is not known, it is desirable to perform a few preliminary tests under conditions such as set forth in the Examples hereinafter to determine whether a one step or a two-step process should be used.
As an example of the benefits that can be realized by use of the two-step procedure, controlled potential electrolysis of dimethyl disulfide in the presence of acenaphthylene in the absence of an organic nucleophilic base resulted in copious polymer formation. But when the same electrolysis procedure was conducted in the additional presence of pyridine, an oxidation-resistant adduct of this invention formed which on eliminative aromatization in the second step resulted in the production of 1-methylthioacenaphthylene in 76% yield using electrochemical reductive elimination.
Anthracene does not form a pyridinium adduct under these conditions, and thus use of an organic nucleophilic base is not of help in this instance. It is believed that the inhibition of adduct formation in this case may be explained by the lack of formation of thiiranium salts which precede the adduct formation.
Organic Thiating Agent
The organic disulfides utilized in the practice of this invention can be represented by the formula R-S-S-R where R is an organic group. Although there are two organic groups in the molecule, when the organic groups are the same, such compounds may be named, for example, as methyl disulfide instead of dimethyl disulfide. The organic groups of the organic disulfides utilized in the practice of this invention can be hydrocarbyl groups (i.e., the organic groups consist of carbon and hydrogen), or they can be functionally-substituted hydrocarbyl groups wherein the substituent(s) on the hydrocarbyl group do not interfere with the formation of the organo thiating agent or the reactions involved in forming the organothio arene product being produced. Tertiary hydrocarbyl disulfides are not desired as organic disulfides in the practice of this invention because they have been reported not to generate thiating agents; see Elothmani et al., J Chem. Soc., Chem. Comm., 1993, 715. Because alkenes are known to react with thiating agents, nonaromatic unsaturation is also undesirable in the organic disulfide. Therefore it is preferable that the organic disulfide used is a hydrocarbyl disulfide in which the hydrocarbyl groups are free of non-aromatic unsaturation.
The hydrocarbyl groups of the disulfides used in the practice of this invention can be primary or secondary aliphatic, cycloaliphatic, or aromatic hydrocarbyl groups which are free of non-aromatic unsaturation. Preferably, the hydrocarbyl groups will each contain up to about 18 carbon atoms, and more preferably, up to about 8 carbon atoms. Of the dihydrocarbyl disulfides, preferred are the primary alkyl disulfides in which the alkyl groups can be the same or different and can be linear or branched.
The organic disulfides in which the organic groups contain one or more innocuous functional substituents are compounds in which the substituents are, for example, halogen atoms, alkoxy groups, aryloxy groups, nitro groups, esterified carboxyl groups, nitrile groups, heterocyclic groups in which the heteroatom(s) is/are oxygen and the like. Examples of suitable organic disulfides include dimethyl disulfide, diethyl disulfide, bis(2-hydroxyethyl) disulfide, dipropyl disulfide, bis(3-carboxypropyl) disulfide, diisopropyl disulfide, di-n-butyl disulfide, di-sec-butyl disulfide, bis(2,2,4,4-tetramethylcyclobutyl) disulfide, bis(heptafluorocyclobutyl) disulfide, dipentyl disulfide, dicyclopentyl disulfide, dicyclohexyl disulfide, dicyclooctyl disulfide, di-o-tolyl disulfide, di-p-tolyl disulfide, bis(3-nitrophenyl) disulfide, di-1-naphthyl disulfide, di-2-naphthyl disulfide, and the like. A preferred group of dihydrocarbyl disulfides are primary hydrocarbyl disulfides, RCH2xe2x80x94Sxe2x80x94Sxe2x80x94CH2R, where R is a hydrocarbyl group, preferably having up to about 17 carbon atoms, more preferably up to about 7 carbon atoms, and in which there is no non-aromatic unsaturation. Particularly preferred dihydrocarbyl disulfides are dimethyl disulfide and diethyl disulfide, especially dimethyl disulfide.
Arene Substrate
A wide variety of aromatic compounds are suitable as organothiatable substrates, provided that the site to be organothiated has a hydrogen atom as its substituent, and that other constituents, if any, present in the compound to not interfere with the desired reaction(s). The aromatic compounds may be heterocyclic compounds such as those containing oxygen or sulfur, or homocyclic compounds. In either case, the aromatic compounds may be mononuclear (i.e., single ring compounds) or polynuclear. Aromatic compounds with fused ring systems are preferred. Examples of homocyclic aromatic compounds deemed suitable for use in the practice of this invention include benzene, naphthalene, anthracene, phenanthrene, acenaphthene, acenaphthylene, indene, isoindene, fluorene, chrysene, pyrene, triphenylene, toluene, xylene, biphenyl and similar compounds. Heterocyclic aromatic compounds deemed suitable include thionaphthalene, xanthene, furan, benzofuran, isobenzofuran, and the like. Those arenes most preferred are anthracene, phenanthrene, and acenaphthylene.
Examples of substituents (other than hydrogen atoms) which may be present on the aromatic ring include, but are not limited to, hydroxy groups, hydrocarbyl groups, and hydocarbyloxy groups. Aromatic rings containing as fuictional substituents only deactivating substituents are not expected to react with an organothiating agent. Deactivating substituents, such as nitro groups and carboxyl groups, may be present under one of the following two conditions: first, when an activating substituent is also present on the aromatic ring to be organothiated, as in, for example, p-nitrophenol or 2-methyl-3-nitronaphthalene; second, when reaction with a different aromatic ring is desired, for a compound with two or more aromatic rings, as in, for example, 3-nitrofluorene. Substituted homocyclic aromatic compounds that may be used include methoxybenzene, thioanisole, acenaphthalene, 2-isopentoxynaphthalene, 7-isopropyl-1-methylphenanthrene, 3-methylindene, 1,2-diphenylindene, 5,6-dimethylchrysene, 2,7-dimethylpyrene, 1-acetylpyrene, 1,3-dimethylanthracene, 9,10-dibenzylanthracene, 4,4xe2x80x2-dimethoxybiphenyl, 2,4xe2x80x2-diethoxy-3,3 xe2x80x2-dimethylbiphenyl, and the like. Substituted heterocyclic aromatic compounds include, for example, 2-octylthiophene, 9-phenylxanthene, 2-benzoylbenzofuran, 2-tert-butylfuran, 2,5-dimethoxyfuran, and similar compounds. Typically, the aromatic compound used as the substrate will contain up to about 40 carbon atoms.
Organic Nucleophilic Bases
Although pyridine is the preferred organic nucleophilic base for use in those embodiments where a two-step is to carried out, other compounds of this type can be used. A few examples include 2-picoline, 3-picoline, 4-picoline, 2,4-lutidine, 2,6-lutidine, 3,4-lutidine, 3-ethylpyrine, 4-ethylpyridine, aldehydine, xcex1-collidine, xcex2-collidine, xcex2-parvoline, 4-methoxypyridine, quinoline, lepidine, 8-methylquinoline, 5,8-dimethylquinoline, xcex2-cytisolidine, and the like.
Proportions
Variations are possible in the proportions in which the disulfide and the arene substrate are used in the organothiation reaction. Each mole of organic disulfide has in theory the capability of organothiating two organothiatable sites in one mole of the substrate. Thus, in situations where there is only one organothiatable site in the substrate, or where the substrate has more than one organothiatable site and all such sites are to be organothiated, the relative proportions of the disulfide and of the substrate can be widely varied from a stoichiometric deficiency of the disulfide to a stoichiometric excess of the disulfide relative to the substrate. To minimize the amounts of unreacted materials to be separated from the organothiated product (when such separation is desired), the organothiating reagent and such substrate are preferably mixed together in approximately stoichiometric proportions so that the conversion of both reactants to desired product is essentially complete.
When the substrate contains a plurality of organothiatable sites, but less than all are to be organothiated, it is desirable to employ an amount of the disulfide that is somewhat less than, equivalent to, or only slightly more than the stoichiometric amount required to effect the extent of organothiation desired. For example, when more than one organothiatable site is present in the substrate, and mono-organothiation is desired, amounts of organic disulfide below one mole per mole of substrate can be used, although it is usually preferable to use approximately one mole or a small excess (e.g., up to about 1.5 moles) of the disulfide per mole of such substrate. But when more than two organothiatable sites are present in the substrate, and di-organothiation is desired, the preferred amount of disulfide is approximately 2 to about 2.5 moles per mole of such substrate. However, if using less than two moles of disulfide in such a situation, at least an amount above one mole of the disulfide should be used per mole of the such substrate to ensure that at least some di-organothiated product will be produced. Thus in general, when the number of organothiatable sites is greater than the number of sites that are intended to be organothiated, amounts of disulfide used should be such as to provide a sufficient conversion to the desired product without producing an undesirable amount of unwanted by-products. However, while not a preferred embodiment of this invention, under some circumstances, a mixture of products may be desired, and in such case the proportions are adjusted accordingly. The most preferred proportion used is about one mole of organic disulfide per mole of sites to be organothiated.
When an organic nucleophilic base is used, it will typically be used in proportions at least equivalent to the number of moles of arene present in the mixture being subjected to anodic oxidation. Preferably the base will be present in an amount in the range of about I to about 2 moles per mole of arene.
Solvent
A wide variety of known electrochemical solvents can be employed in the practice of the electrochemical oxidation of this invention. For a discussion of such solvents, see for example, H. Lund and M. Baizer, Organic Electrochemistry; an Introduction and Guide, Marcel Dekker pubs., New York, 1991. Among suitable solvents are polar chlorohydrocarbons such as methylene chloride and polar aprotic solvents such as acetonitrile. Preferred are inert polar solvents, which preferably have an electric dipole moment of at least about 1xcexc as measured in the gaseous state or in benzene or 1,4-dioxane. See, for example, A. L. McClellan, Tables of Experimental Dipole Moments, 1963.
Preferred solvents are liquid organic polar solvents which are suitable for sustaining the electrolysis reaction. These include organic compounds with carbon groups having between 2 and about 10 carbon atoms, more preferably those having 2 to about 5 carbon atoms. Examples of suitable dipolar aprotic solvents with high polarity (e.g., with dipole moments of at least about 2.2xcexc and preferably at least about 3xcexc) include but are not limited to acetonitrile, propionitrile, benzonitrile, N,N-dimethyl formamide, N,N-diethyl formamide, dimethyl sulfoxide, sulfolane, N,N-dimethyl acetamide, N,N-diethyl acetamide, propylene carbonate and the like. Of such solvents, acetonitrile is most preferred.
Supporting Electrolvte
Various known supporting electrolytes can be used in the electrochemical oxidation process. These include appropriate alkali metal salts that are soluble in the solvent used, such as alkali metal perchlorates and alkali metal triflates. Quaternary ammonium salts can also be used. In order to properly support current flow in the solution, the supporting electrolyte is typically present in the solution at least as a 50 millimolar solution, and preferably as an approximately 0.1 molar solution. Further details concerning supporting electrolytes and their use are known and reported in the literature. See for example, H. Lund and M. Baizer, Organic Electrochemistry; an Introduction and Guide, Marcel Dekker pubs., New York, 1991.
Reaction Conditions for Anodic Oxidation
The electrochemical process of this invention can be readily conducted in a two compartment electrochemical cell using as a working electrode (anode) a cylinder of platinum gauze, and as an auxiliary electrode (cathode) an aluminum cylinder. A silver wire can serve as the reference electrode. The applied potential is typically in the range of about +0.7 to about +1.2 volts. For further discussion of electrochemical cells and techniques, see, for example, A. Fry, Synthetic Organic Electrochemistry, John Wiley and Sons, New York, 1989.
Typically, the electrochemical process is initiated at about room temperature although higher or lower temperature conditions can be employed if desired. Pressure normally is of no consequence in this reaction, and thus the reaction is usually performed at the atmospheric pressure prevailing at the time of the operation.
Eliminative Aromatization
Preferred adducts of this invention may be represented by the formula:
RS-CY-CX-⊕NB
where RS is an organothio group having up to about 18 carbon atoms, and more preferably, up to about 8 carbon atoms, and in which organic portion, R, is a primary or secondary organic group, preferably a primary or secondary hydrocarbyl group, more preferably a primary alkyl group, still more preferably a methyl or ethyl group, and most preferably a methyl group; CY-CX is a 5 or 6-membered cycloaliphatic group having either 5 carbon atoms or 6 carbon atoms in a homocyclic ring system, or a 6-membered ring having 5 carbon atoms and one oxygen, nitrogen, or sulfur hetero atom; and ⊕NB is an organic base.
When it is desired, as in a two-step processes of this invention, to convert such an adduct into an organothioarene
RS-Ar
where RS is as defined above, and Ar is an univalent aromatic group derived from an arene by loss of a ring hydrogen atom, the adduct is subjected to an eliminative aromatization step. This can be conducted either non-electrochemically or electrochemically. In a non-electrochemical eliminative aromatization step, the adduct is treated with a suitable base such as an alkali metal alkoxide in an anhydrous alcohol medium or with an organic base such as an amidine in an inert medium such as an ether. Use of sodium methoxide in anhydrous methanol, or either 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in tetrahydrofuran, serve as typical examples of such basic treating agents.
The following examples are presented for purposes of illustration and are not intended to impose limitations on the scope of this invention. In these experiments 1H and 13C NMR spectra were recorded in the solvent indicated with 0.5% TMS as internal standard using a Bruker AM 250 spectrometer at 250.13 and 62.9 MHz, respectively. EI-MS were done using a Hewlett Packard HP5988A mass spectrometer. FAB mass spectra were measured using a JEOL XH110A instrument. Elemental analysis was performed by Desert Analytics, Tucson, Ariz. Thick layer chromatography was done using Analtech Uniplate GF 2000 silica gel plates. Column chromatographywas accomplished with silicagel (75-125 j.1m) supplied by Analtech, Newark, Del.
The electrochemical oxidations were done using three electrodes in a two-compartment cell and a PAR-362 potentiostat. A Pt gauze (3xc3x975 cm) was used as the anode and Al foil (5xc3x9710 cm) as the cathode.